Our laboratory and clinical research efforts have been devoted to studying the cellular immune reactivity against established cancers in experimental animals and in humans and the translation of these findings to the development of effective immunotherapies for patients with cancer. Our early studies demonstrated that the systemic administration of IL-2 could lead to durable objective cancer regressions in patients with metastatic melanoma or metastatic kidney cancer. These clinical studies of IL-2 administration led to studies to identify the immune cells capable of recognizing cancer. We described tumor infiltrating lymphocytes (TIL) in both mice and humans that could be grown from the stroma of solid tumors and have been used to develop adoptive cell transfer therapies. Adoptive cell transfer (ACT) has several theoretical advantages compared to other immunotherapy approaches. In cell transfer therapies highly selected cells with high avidity for recognition of tumor antigens can be activated ex vivo to exhibit anti-tumor effector function, expanded to large numbers, and tested in vitro to identify the exact subpopulations and effector functions that are required for cancer regression in vivo. Perhaps most importantly it is possible to manipulate the host prior to the cell transfer to provide an altered environment for the transferred cells. Naturally occurring tumor infiltrating lymphocytes (TIL) expanded in vitro and administered to melanoma patients resulted in objective responses (RECIST) in 56% of 194 patients including complete regressions in 24% of patients who remain ongoing disease-free with median potential follow up exceeding seven years. To determine the antigens recognized by TIL we developed an approach based on deep exomic and transcriptome sequencing of the cancer and immunologic testing of TIL or peripheral lymphocytes to generate T-cells that recognized immunogenic mutations. TIL from 22 patients with metastatic melanoma recognized 54 random somatic mutations none of which were shared among different melanomas. We next extended these studies to patients with common epithelial cancers that cause 90% of deaths from cancer and showed that 81 of 99 (82%) patients with a variety of human cancer types including esophageal, colorectal, bile duct, gastric, pancreatic, ovarian, cervical and lung cancer contained T-cells that recognized 197 neoantigens all of which were unique except for KRAS (2 patients). Targeting unique cancer mutations has now extended the reach of ACT immunotherapy and was used to mediate objective regressions in selected patients with chemorefractory metastatic cancers of the bile duct, colon, cervix, and breast. In more recent studies, we have begun clinical protocols utilizing the transfer of autologous lymphocytes transduced with genes encoding T-cell receptors reactive with defined mutated antigens. Autologous T-cells can be used to provide a highly personalized immunotherapy for cancer patients refractory to conventional cancer treatments.